Extracellular senile plaques and phosphorylated tau-associated intraneuronal neurofibrillary tangles (NFTs) are the two classical microscopic pathologies of Alzheimer's disease (AD). Senile plaques comprise a dense core of amyloid-β (Aβ) that is surrounded by dystrophic neurites as seen in Selkoe D J (2004) Cell biology of protein misfolding: the examples of Alzheimer's and Parkinson's diseases. Nat Cell Biol 6: 1054-1061. Aβ is a 39-43 amino acid proteolytic product of a larger amyloid precursor protein (APP). APP is an integral membrane protein processed by the proteases α-secretase or β-secretase to produce α-C terminal fragment (CTF-α) or β-C terminal fragment (CTF-β), respectively. These fragments are subsequently cleaved by α-secretase to produce P3 or Aβ respectively, and a cytoplasmic tail dubbed APP-intracellular domain (AICD). APP proteolysis also releases soluble forms of APP (sAPPα- and sAPPβ), and these soluble APPs may also now be considered biomarkers for AD (P Lewczuk et al., Soluble amyloid precursor proteins in the cerebrospinal fluid as novel potential biomarkers of Alzheimer's disease: a multicenter study Mol Psychiatry. 2010; 15:138-45). On the other hand, monomeric Aβ (4.3 kDa molecular weight) self-assembles into oligomers (Selkoe D J (2004) Cell biology of protein misfolding: the examples of Alzheimer's and Parkinson's diseases. Nat Cell Biol 6: 1054-1061 and Hardy J, Selkoe D J (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297: 353-356). These oligomers eventually deposit as large fibrils in extracellular space, which assemble as amyloid plaques. Although the precise mechanisms by which Aβ may induce neurotoxicity are still unknown. Several studies have proposed these mechanisms include calcium influx, generation of reactive oxygen species (ROS), nitric oxide (NO) production and increased phosphorylation of tau.
The US Food and Drug Administration has approved five drugs (i.e., tacrine, donepezil, rivastigmine, galantamine and memantine) for the treatment of AD (Lleó A, Greenberg S M, Growdon J H (2006) Current pharmacotherapy for Alzheimer's disease. Ann Rev Med 57: 513-533), but they produce only mild, symptomatic relief and do not halt progression of dementia. Therefore there is a need for alternative drugs for the treatment of AD. One source of phytotherapeutic agents is Huang-Lian-Jie-Du-Tang (HLJDT), a traditional Chinese medicine (TCM) achieving popularity for its therapeutic application.
HLJDT is a famous TCM formula widely used in treating stroke and dementia. It is composed of four herbs, namely: Rhizoma coptidis (RC) (Coptis chinensis Franch, or Huang Lian in Chinese), Radix scutellariae (RS) (Scutellaria baicalensis Georgi, or Huang Qin in Chinese), Cortex phellodendri (CP) (Phellodendron amurense, or Huang Bai in Chinese) and Fructus gardeniae (FG) (Gardenia jasminoides Ellis, or Zhi Zi in Chinese), in a 3:2:2:3 dry weight ratio. As stated in the traditional Chinese medicinal book Wai-Tai-Mi-Yao, RC, RS, and CP are major ingredients of HLJDT, and FG functions as an adjuvant constituent to support the effect of the principal ingredients. All traditional Chinese literatures so far document that HLJDT formula must consist all four herbs.
HLJDT has been used to treat senile dementia, inflammation, digestive system upsets, and cerebrovascular disease in China (Chen G H, Shan P, Qiu X (2007) The clinical study on Huanglianjiedu decoction on for patients with senile dementia, the type of hyperactivity of heart-fire and liver fire in TCM. Zhongguo Zhongyi Jizheng 16: 386-387). HLJDT has been used to treat various clinical symptoms linked with stroke and with vascular dementia in Japan (Otomo E, Togi H, Kogure K (1991) Clinical usefulness of TSUMURA Orengedokuto for the treatment of cerebrovascular disease: a well-controlled study comparing TSUMURA Orengedokuto versus Ca hopantenate, using sealed envelopes for allocation. Geriatric Medicine 29: 121-151 and Ito E, Takahashi A, Kazuya F (1991) Clinical effectiveness of TSUMURA Orengedokuto in the treatment of cerebral infarction. Geriatric Medicine 29: 303-313). In a Japanese clinical study, Okamoto H et al., (2013) Orengedoku-to augmentation in cases showing partial response to yokukan-san treatment: a case report and literature review of the evidence for use of these Kampo herbal formulae. Neuropsychiatr Dis Treat. 2013; 9:151-155, the addition of HLJDT to yokukan-san (Japanese traditional herbal medicine) exerted the same efficacy as aripiprazole (antipsychotics) in controlling aggressiveness in an Alzheimer's type dementia patient without any adverse effects.
Preclinical reports in Kondo Y, Kondo F, Asanuma M, Tanaka K, Ogawa N (2000) Protective effect of oren-gedoku-to against induction of neuronal death by transient cerebral ischemia in the C57BL/6 mouse. Neurochem Res 25: 205-209, Wang S, Jiang N, Zhou W X, Zhang Y Y (2007) Effect of Huanglian Jiedutang on expression of hippocampus proteomics in senescence accelerated mouse. Zhongguo Zhong Yao Za Zhi 32: 2289-2294, and Qiu X, Chen G H, Wang T (2011) Effects of huanglian jiedu decoction on free radicals metabolism and pathomorphism of the hippocampus in App/PS1 double transgenic mice. Zhongguo Zhong Xi Yi Jie He Za Zhi 31: 1379-1382 provide evidence that HLJDT can improve cerebral blood flow; it potently inhibits lipid peroxidation in the brain and thus preserves energy metabolism in the brain. Both ethanolic extracts and aqueous extracts of HLJDT can ameliorate the cognitive impairments induced by cerebral ischemia and central cholinergic dysfunction in animal models. Recently, Durairajan S S K, Liu L F, Lu J H, Chen L L, Yuan Q, Chung S K, Huang L, Li X S, Huang J D, Li M (2012) Berberine ameliorates β-amyloid pathology, gliosis, and cognitive impairment in an Alzheimer's disease transgenic mouse model. Neurobiol Aging 33: 2903-2919 shows that berberine, a compound in HLJDT, can significantly reduce the Aβ load in a transgenic Alzheimer's disease model by regulating APP processing. However, the exact mechanism underlying HLJDT-mediated cognitive improvements is not known. In the context of AD, there is a study of HLJDT in AD mice by Qiu X, Chen G H, Mei G, Wang Y G. (2011) Effects of huanglian jiedu decoction on free radicals metabolism and pathomorphism of the hippocampus in App/PS1 double transgenic mice Zhongguo Zhong Xi Yi Jie He Za Zhi 31: 1379-1382. Qiu et al. reported that HLJDT reduced Aβ plaques and improved memory in APP/PS-1 mice, but the authors did not mention the quantification of Aβ load. Qiu et al. also reported that HLJDT reduced APP mRNA level but did not measure the effect of HLJDT on the protein level of full length (F1)-APP, Aβ and soluble forms of APP, namely, sAPPα and sAPPβ.
Citation or identification of any reference in this section or any other section of this application shall not be construed as an admission that such reference is available as prior art for the present application.